Patient and General Population Preferences Regarding the Benefits and Harms of Treatment for Metastatic Prostate Cancer: A Discrete Choice Experiment

Take Home Message There is substantial preference heterogeneity between patients regarding the expected survival benefits and potential adverse effects of systemic treatment for metastatic hormone-sensitive prostate cancer. Patients’ preferences regarding survival and treatment-related adverse effects should be explicitly discussed in clinical practice.


Introduction
Patient preferences are an important part of patientcentered care and there is growing interest in incorporating preference information in regulatory assessments of novel treatments [1][2][3][4][5][6][7]. In recent years, changes in the treatment landscape have vastly increased the number of treatment options for metastatic prostate cancer (mPC) [8][9][10][11]. Various treatment options are available for metastatic hormone-sensitive prostate cancer (mHSPC) in addition to androgen deprivation therapy, including chemotherapy with docetaxel, second-generation hormonal therapy with abiraterone acetate, enzalutamide, or apalutamide, radiotherapy, and combined approaches [12][13][14][15][16]. However, this poses challenges in choosing a treatment on the basis of its expected benefits and potential harms. Since prostate cancer is the most frequent cancer among men [17], better knowledge about the treatment outcome-related preferences of patients with mPC is essential to optimally guide care and support these patients in clinical practice.
Preference studies are a well-established method for eliciting patient preferences [18,19]. To date, only little such research has been conducted in mPC [20,21]. Previous studies have shown that overall survival, progression-free survival, health-related quality of life (HRQoL), pain control, mode of administration, and the risk and severity of various potential adverse effects of treatment are important to patients with mPC [22][23][24][25][26][27][28][29][30]. Given the relevant variation between studies, it remains unclear which factors are most important for treatment decisions [20,21]. Methodological discussions are ongoing on whether it is most appropriate to elicit preferences among individuals with or without experiences of the decision and its consequences, such as adverse effects during cancer treatment [2,31]. In mPC, no study so far has addressed whether preferences differ between these groups [20,21].
Furthermore, previous studies have not explicitly evaluated whether and how preferences vary between individual patients and patient subgroups [21]. However, such preference heterogeneity is highly important in clinical practice, since decision contexts with variable preferences are most likely to be preference-sensitive, warranting individualized treatment discussions [2,32].
The aim of our study was to evaluate the preferences of patients with mPC and men from the general population regarding the attributed benefits and harms of systemic treatment for mHSPC. The main objectives were to elicit preference weights and estimate the trade-offs involved, compare preferences between the two populations, and evaluate preference heterogeneity between individuals and population subgroups.

Study design
We conducted a cross-sectional preference survey between November 2021 and August 2022, following the good practice guidelines of the International Society For Pharmacoeconomics and Outcomes Research [19,33,34]. The study protocol was registered on the Open Science Framework platform [35]. The research project was evaluated by the

Experimental design
We used a discrete choice experiment (DCE) approach, which is a method commonly used to quantitatively elicit preferences [18,19,33].
The DCE design was based on a qualitative exploration of patient preferences in mPC and pilot testing (Supplementary material). In brief, we conducted a systematic literature review of patient preferences to identify patient-relevant attributes of treatment for mPC [21]. We also con-

Survey administration
The study was administered using an online survey platform. Patients with mPC had the additional option of completing a paper-based survey and requesting support via telephone. In addition to the DCE, the survey questionnaire included questions on sociodemographic characteristics, current health status (assessed via a visual analog scale [VAS]), and comorbidities. In addition, patients with mPC were asked for details regarding their initial diagnosis and metastasis, current and previous treatments, and any adverse effects of treatment they experienced.
Men from the general population were surveyed using almost identical questionnaires, with specific questions on whether they had personal or professional experiences with cancer (ie, any personal experiences with prostate cancer or cancer more generally via affected relatives or friends, or professional experiences in treating or caring for individuals affected by cancer).
An example DCE choice task is provided in Fig. 1. The study documentation included a brief explanation of the aims of the study, a description of the (hypothetical) decision-making scenario, and an instruction on completing the choice tasks. We also presented participants with brief outcome descriptions for all attributes and attribute levels (accessible throughout the entire DCE), and included short cues given within all choice tasks for their reference. A visual representation was used for overall survival benefits, but not for the severity of adverse effects, since we wanted the outcome descriptions to drive participants' choices rather than a visual representation of severity levels.

Statistical analysis
All participants providing at least partial data were included, while indi- To derive preference weights for the different attribute levels, we applied multinomial logit models to the DCE choice data using dummy coding based on random utility theory [18,34,38,39]. First, we explored the data using multinomial logit models with overall survival coded as either a categorical or continuous outcome. To evaluate preference heterogeneity and trade-offs between survival benefits and treatment adverse effects across individuals in the study, we then applied mixed multinomial logit models using overall survival (coded as a continuous outcome) as a random parameter in the primary analysis. Models were estimated on the basis of 100 Halton draws assuming a normal distribution for random parameters. We estimated separate models for the two study participant samples, as well as for the overall sample. Differences in preferences between participant samples and subgroups were evaluated using z-test statistics for coefficients derived from the separate models. We assessed and compared preference heterogeneity by evaluating the estimated standard deviations (SDs) for mean random parameter estimates. We then calculated the marginal rates of substitution to quantify the number of months of survival participants would trade against averting the harms by calculating the ratio of preference weights for adverse effects and a 1-yr increase in overall survival multiplied by 12.
We conducted several sensitivity analyses in which we excluded participants failing the internal validity assessments, estimated alternative models in which all attributes were included as random parameters, and used a 1:1 propensity score-matched subsample of study participants to evaluate differences between populations. We also conducted subgroup analyses to investigate whether there were differences in preferences between participants aged !65 yr and those aged <65 yr, between patients with mPC in different disease stages and with and without prior adverse effect experiences, and between men from the general population with and without personal or professional experiences with cancer. Finally, we conducted a prespecified experimental analysis using a latent class multinomial logit model to investigate whether there is evidence of the presence of two groups with different preferences. The hypothesis was that some individuals may strongly prefer survival and accept adverse effects, while others may more strongly prefer the absence of adverse effects (ie, higher HRQoL) and accept trade-offs regarding survival. We explored participant characteristics that may be associated with latent classes in a descriptive analysis and using multivariable logistic regression.

Sample characteristics
We enrolled an overall sample of 388 individuals, composed of 77 patients with mPC and 311 men from the general population. The participation rate was 65.4% among eligible and invited patients with mPC and 63.1% among eligible men from the general population ( Supplementary Fig. 2). Owing to limited patient enrolment, data from patients with mPC who participated in the pilot testing were included in this analysis (discussed in the Supplementary material).
Participant characteristics in the two populations differed: patients with mPC were older overall (median 73 yr vs 64 yr) and were more likely to be retired (77.6% vs 52.4%), reported lower general health status (median VAS score 75 vs 85), and more frequently reported the presence of medical comorbidities (59.7% vs 46.9%) in comparison to men from the general population (Table 1 and Supplementary Table 4). Further sociodemographic characteristics were broadly comparable between the groups.
In the mPC group, 74.0% had mHSPC and 26.0% had mCRPC. 96.1% reported receipt of treatment for mPC, with a median time on current treatment of 2 yr (interquartile range [IQR] 1-3). While all reported having experience with treatment in the metastatic setting, 69.0% reported ever having experienced adverse effects from treatment. Among men from the general population, 76.1% stated that they have personal or professional experiences with cancer.

Assessment of internal validity
Almost all participants responded correctly to the dominance test (n = 374, 97.1%) and considered both alternatives in their responses (n = 7, 1.8% consistently chose either alternative; Supplementary With respect to harm outcomes, there was strong evidence that participants from both populations had a preference for averting diarrhea, fractures, ischemic heart disease, and rash at all severity levels, as well as moderate fatigue ( Fig. 2 and Supplementary Table 6). For mild fatigue and mild and moderate peripheral neuropathy, evidence of a preference for averting the outcome was insufficient among patients with mPC. Overall, there was no evidence of a difference in preferences between participant samples for any of the harm outcomes.
The number of months of survival that participants were willing to trade against averting different adverse effects differed between the mPC and general population groups ( Table 2). Among patients with mPC, willingness to trade Fig. 2 -Preference weights regarding the benefits and harms of treatment for metastatic prostate cancer, taking into account preference heterogeneity between participants. Preference weights with 95% confidence intervals (CIs) were estimated for patients with metastatic prostate cancer and men from the general population using dummy-coded mixed logit models with overall survival (OS) as a random parameter. Preference weights represent the strength of preference relative to the reference level, with negative values representing a preference for averting the outcome. PN = peripheral neuropathy; IHD = ischemic heart disease. ranged from 1 mo for mild fatigue to 36 mo for very severe ischemic heart disease. The range was from 3 mo for mild diarrhea to 68 mo for very severe ischemic heart disease among general population participants.
Evaluation of preference heterogeneity across participants revealed strong evidence of relevant variability in participants' survival-related preferences both among patients with mPC (SD for preference weight 1.31, 95% CI 0.94-1.68; p < 0.001) and among men from the general population (SD for preference weight 1.04, 95% CI 0.89-1.19; p < 0.001; Supplementary Table 6). While preference heterogeneity was higher among patients with mPC in absolute terms, evidence of a difference between samples was insufficient (test for difference: p = 0.19). Overall, the findings were consistent throughout different sensitivity analyses excluding individuals who failed internal validity assessments, using different models for analysis, and using a propensity score-matched participant subsample for comparisons between population samples (Supplementary  Tables 7-12).

Subgroup analyses
In subgroup analyses stratified by age group, there was insufficient evidence of a difference in survival-related preferences between men aged 45

Latent class analysis
The latent class analysis identified two groups with different sets of preferences among study participants, with strong evidence of a difference between groups (test for difference in survival-related preferences between classes: p < 0.001; Fig. 3 and Supplementary Table 15). The first group, including 76.0% of participants (class 1, n = 295), appeared to have a strong general preference for averting adverse effects and a lower preference for improvement in survival (while there was still strong evidence of a preference for survival benefits). The smaller second group (class 2, 24.0%, n = 93) had a strong preference for survival and showed a lower preference for averting adverse effects of treatment. Analysis of the distribution of participant characteristics in the two groups revealed no evidence that specific characteristics were associated with membership of either group according to descriptive and multivariable logistic regression analyses (Table 3).

Main findings
In this DCE preference study of patient and general population preferences regarding mHSPC treatment, we found that outcome preferences between patients suffering from mPC and men at risk of developing prostate cancer relevantly dif- fer, with a stronger preference for survival benefits among patients with mPC overall. Furthermore, we found substantial heterogeneity in preferences between individuals, and identified two distinct groups of individuals strongly preferring either longer survival or the absence of adverse effects. Meanwhile, we did not find specific participant characteristics associated with belonging to either group, or evidence of differences between subgroups for age, disease stage, experiences with adverse effects, or personal or professional experiences with cancer. Our findings suggest that patient preferences may have a relevant impact on treatment choices in mHSPC. The study shows that the potential adverse effects and their impact on HRQoL need to be equally considered as potential survival benefits. Indeed, the group of participants with a stronger preference for the absence of adverse effects was substantially larger than the group strongly preferring survival. While this does not mean that survival is not important for all patients (there was strong evidence of a survival preference in both groups), it indicates that the balance of benefits and harms is relevant for patients and that decision-making solely based on survival outcomes from clinical trials is likely to be inappropriate. It is thus critical that trials collect and fully report all relevant data, especially regarding adverse effects and HRQoL. Further investigations are necessary to determine the preference sensitivity of decisions in this context, combining information on patient preferences, real-world risks, and treatment effects related to the benefits and harms of mHSPC treatment. Our findings also suggest that preferences are difficult or even impossible to predict for an individual patient. Hence, our study provides strong evidence on the importance of considering and discussing individual patient preferences when making decisions regarding mPC treatment in clinical practice.

Findings in context
Previous studies have quantitatively [22][23][24][25][26][27][28]41,42] and qualitatively [29,30,[43][44][45][46][47] investigated patient preferences related to mPC treatment. While these studies evaluated a wide range of different potential benefits, harms, and other aspects of treatment, evidence regarding the most important benefits and harms of treatment remains unclear [20,21]. Previous studies primarily focused on identifying attributes of the highest importance to patients, which may help to guide treatment discussions in clinical practice [21][22][23][24][25][26][27]41]. However, discussions about preferences   between patients and physicians are most likely to improve patient-centered decision-making in contexts in which there is relevant preference heterogeneity (ie, potentially preference-sensitive decisions) [2,21,32]. In contrast to previous studies, we investigated and demonstrated the presence of preference heterogeneity in the context of mHSPC, thereby providing evidence that no single attribute is likely to be pivotal for treatment decisions in this context. Whether the results from our study can be generalized to other disease contexts remains unclear. One previous study investigating patient preferences related to prostate cancer screening found substantial preference heterogeneity between participants [48]. Given the consistency of our results across participant samples and mPC disease stages, it may be reasonable to assume that substantial preference heterogeneity also exists more generally in mPC. Depending on their individual preferences combined with personal circumstances, life expectancy, and disease characteristics, some men with mHSPC may prefer to forego systemic treatment to avoid its potential harms. Therefore, while further research across different stages in mPC is necessary, guidelines in this context should ensure that they are sensitive and adaptive to differences in preferences between patients.
At a methodological level, preference heterogeneity is frequently discussed and statistical models accounting for such heterogeneity are often applied in studies [49,50]. However, preference heterogeneity is rarely directly addressed or reported quantitatively in the literature [49,50]. Furthermore, discussions are ongoing about whether it is most appropriate to measure the preferences of individuals from the general population at risk of facing the decision later, patients currently facing the decision, or patients with past experiences with the decision and its consequences [2,31]. We attempted to address these questions by explicitly evaluating heterogeneity and comparing preferences between men at risk and men with past experiences, demonstrating relevant differences between individuals and populations. On the basis of our findings, future preference studies may benefit from a more comprehensive evaluation of preference heterogeneity.
Given the increasing interest in preference research to guide clinical decisions, regulatory assessment, and industry processes [2,6,7,31,49], it is important to consider how preference information from studies is used to guide clinical or policy decisions. Study designs and methods may differ according to their specific objectives and need to be interpreted in light of the respective stage along the medical product life cycle and the processes that should be informed [2,21,51,52]. This study was designed to inform clinical decisions and to gather experiences for the use of preference information in benefit-harm assessment and health technology assessment, similar to case studies by the Innovative Medicines Initiative Patient Preferences in Benefit Risk Assessments During the Drug Life Cycle (IMI-PREFER) consortium [7]. While further experiences and methodological developments are necessary, findings from this study strongly support the implementation of shared decisionmaking based on patient preferences and may serve as a basis for developing clinical decision-making tools for clinical practice.

Limitations
Some limitations need to be considered when interpreting the results from this study. First, the recruitment strategies we used may have led to selection effects. While this may have influenced our results, the direction of potential biases is difficult to estimate. Since we could not collect data for individuals not participating in this study, we were unable to evaluate potential differences between participants and men not participating in the study. Furthermore, we sought the preferences of men residing in Switzerland only, whose preferences may be culturally different to those of men in other countries or of other ethnicities [53][54][55]. We did not ask for information on ethnicity or specific cultural elements beyond the language region in our study. In addition, patient preferences may vary across other health care contexts with differing access to care or in populations with different levels of baseline comorbidity. However, average preference weights corresponded approximately to what we had expected on the basis of previous studies conducted in other countries. Moreover, we deem it unlikely that a more representative or a more international sample of patients with mPC or the general population would have relevantly altered our findings regarding the presence of preference heterogeneity. Hence, we also consider our key results to be broadly generalizable in an international context. Second, we did not reach the desired size for the mPC sample (discussed in the Supplementary material). As a result, statistical power may have been too low to detect differences in preference heterogeneity in comparison to the general population or in preferences between patient subgroups with different disease stages or adverse effect experiences. Third, it is possible that the cognitive burden of the DCE may have led to inconsistent choices, declining concentration, or nonparticipation by individuals who are older or cognitively impaired. While we aimed to enroll as broad a study population as possible and ensure adequate preparation, instruction, support, and time for completion of the questionnaires, this may still have affected our results. Finally, as is common in DCEs, stated choices in hypothetical scenarios may not reflect the true choices of participants, and it is possible that other attributes not included in the DCE (ie, further benefit and harm outcomes, or other aspects such as mode of administration or cost of treatment) may also have a relevant impact on patients' treatment decisions.

Conclusions
This study demonstrated relevant differences in preferences between individuals regarding the attributed benefits and harm of treatment for mHSPC. This information is crucial for clinical practice and the development of clinical practice guidelines, since it highlights the importance of explicitly taking patients' individual preferences into account when making patient-centered treatment decisions. The study adds evidence on preference heterogeneity in the context of mPC, which may be important for the approval of novel treatments and health technology assessment. Future research may draw from this work to develop clinical decision-support tools and examine preference heterogeneity in other cancer settings.
Author contributions: Dominik Menges had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.
Acquisition of data: Menges, Piatti.
Analysis and interpretation of data: All authors.
Financial disclosures: Dominik Menges certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Aurelius Omlin has received institutional fees for an advisory role for Astellas, AstraZeneca, Bayer, Janssen, Molecular Partners, MSD, Pfizer, Roche, and Sanofi Aventis, personal fees for an advisory role for Astellas, AstraZeneca, Bayer, Janssen, Merck, MSD, and Novartis, institutional research support from Teva and Janssen, and travel support from Astellas, Bayer, Janssen, and Sanofi Aventis, and participates in speaker bureaus for Astellas, Bayer, and Janssen. Richard Cathomas has acted in an advisory role for Astellas, AstraZeneca, Bayer, BMS, Debiopharm, Ipsen, Merck, MSD, Janssen, Pfizer, Roche, and Sanofi, and has received honoraria from Astellas, BMS, and Janssen. Stefanie Fischer has received institutional fees for an advisory role for Ipsen and for speaker bureau participation for Janssen. Christian Rothermundt has received institutional fees for a consulting/advisory role for Bayer